Pathways to retinal regeneration

Pathways to retinal regeneration. (A) Zebrafish are able to completely regenerate their retina via Müller glia. In the uninjured retina, Müller glia is kept quiescent by inhibiting the expression of the genes that control regeneration through Notch signaling and repression by the transcription factor Six3b and the microRNA let7, amongst others. During retinal injury, cell death and inflammation lead to the release of cytokines and growth factors (especially TNFα), which activate receptors and kinases in the Müller glia, leading to activation of β-catenin and phosphorylation of the transcription factor Stat3, which in turns leads to the production of the transcription factor ascl1 and lin28 microRNA, and the activation of the genes that control Müller glia division and dedifferentiation. lin28 also inhibits the production of let7, releasing the inhibition of this pathway. Expression of the transcription factor Pax6b (normally inhibited by the microRNA mi203), allows the amplification and production of retinal progenitors which are then able to redifferentiate into any retinal neurons or Müller glial cells. (B) In medaka fish, lack of production of Sox2 after the production of retinal progenitors restricts their fate to photoreceptors and does not allow the production of other cell types, including new Müller glia. (C) In mice and other mammals, retinal injury does not lead to expression of ascl1 and the rest of regeneration-related genes. Instead Müller glia activate the production of intermediate filaments and increase their size (reactive gliosis) and do not lead to the production of new retinal cells or injury repair. (D) Retinal regeneration can be stimulated in mice by artificially overexpressing ascl1 and inhibiting epigenetic changes (histone deacetylation in particular). With this treatment, Müller glial cells are able to divide and produce retinal progenitors, but their fate is restricted to bipolar and amacrine cells.

Publication

Leveraging Zebrafish to Study Retinal Degenerations. (2018) Juan M. Angueyra, et al. Front Cell Dev Biol. 2018;6:110. Figure: F2. All organisms Bos taurus Mus musculus Homo sapiens Rattus norvegicus Capra hircus Cavia porcellus Oryctolagus cuniculus Danio rerio Xenopus laevis

Disease mentions